Prognostic value of inflammation-related biomarkers in gastric cancer

Gastric cancer is the second most common cause of cancer-related mortality worldwide. The poor prognosis largely results from late diagnosis, often occurring when disease is already at an advanced stage. At the time of diagnosis, treatment with curative intent is possible for less than half of all patients. Currently, the only curative treatment is radical surgery. Despite the decreased incidence of gastric cancer in developed countries given changes in lifestyle and the treatment of Helicobacter pylori (H. pylori) infection, prognosis remains poor. More precise knowledge regarding the underlying pathophysiology is needed in order to allow for earlier diagnosis and to improve prognosis. Chronic inflammation of the gastrointestinal tract mucosa predisposes individuals to cancer with several proteins contributing to the crosstalk between inflammation and cancer. Matrix metalloproteinases (MMPs) can promote cancer cell invasion and metastasis by degrading the extracellular matrix. In previous studies, a high expression of matrix metalloproteinase 14 (MMP14) associated with metastasized gastric cancer and a poor outcome. Prospero homeobox protein 1 (PROX1) is a transcription factor functioning in cell fate determination and organ development, and also expressing in various cancers. PROX1 acts context dependently either as an oncogene or as a tumor suppressor. PROX1 was recently shown to inhibit the transcription of MMP14 in several cancers, although it was not examined in gastric cancer. Toll-like receptors (TLRs) are pattern recognition receptors essential to innate immunity. They express in malignant diseases, activated by damage-associated molecular patterns. Tumor-associated trypsin-2 (TAT-2) and its inhibitor, tumor-associated trypsin inhibitor (TATI), can promote carcinogenesis by activating endothelial growth factor receptors, pro-urokinase, and MMPs. In addition, C-reactive protein (CRP) is a well-known and widely used inflammatory biomarker. Elevated preoperative CRP levels have been attributed to a poor outcome in colonic, pancreatic, and gastric cancers. Therefore, this study aimed to evaluate the significance of these potential prognostic biomarkers in gastric cancer. The cohort consisted of 313 individuals operated on between 2000 and 2009 for histologically confirmed gastric adenocarcinoma in the Department of Surgery, Helsinki University Hospital, Finland. Preoperative blood samples were collected from 240 patients with gastric cancer and from 48 control patients with benign disease. Tissue MMP14, PROX1, TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 expression levels were studied using immunohistochemistry. Soluble serum MMP14 levels were determined using an enzyme-linked immunosorbent assay. Serum TAT-2, TATI, and plasma CRP levels were determined using time-resolved immunofluorometric assays. A high MMP14 expression, whether in tissue samples or serum, predicted a poor outcome and a high serum MMP14 remained an independent prognostic factor in the multivariate survival analysis. A high tissue MMP14 predicted an unfavorable outcome, particularly among those with a low PROX1 level. Furthermore, a high tissue TLR5 expression predicted a better outcome. We also found that TLR1, TLR2, TLR4, TLR7, and TLR9 did not serve as prognostic biomarkers across the entire cohort. Nevertheless, TLR9 served as a prognostic factor among those with stage II disease and TLR7 among those with stage III disease. High serum TAT-2 and TATI both identified patients with poor prognoses, with TATI remaining significant in the multivariate survival analysis. Moreover, serum TAT-2 levels were higher among patients with gastric cancer than among controls. Interestingly, preoperative CRP did not serve as a prognostic biomarker in this cohort of gastric cancer patients. None of the biomarkers studied are currently in routine clinical use in gastric cancer. However, this thesis shows that several of the biomarkers examined hold potential as prognostic factors in gastric cancer and represent promising candidates for further investigation. In conclusion, survival seems worse among gastric cancer patients with a high tissue MMP14 expression, particularly with concurrent low PROX1 levels. Thus, a high serum MMP14 may serve as an independent unfavorable prognostic biomarker. Survival appears better among patients with a high tissue TLR5 expression. Additionally, high tissue TLR7 and TLR9 expressions appear to serve as favorable prognostic biomarkers in certain subgroups. In addition, a high serum TATI may serve as an independent unfavorable prognostic factor. Lastly, serum TAT-2 levels appear higher among patients with gastric cancer than among controls and a high TAT-2 may serve as a marker of an unfavorable prognosis.